Method and apparatus for tissue protection against ischemia using remote conditioning

ABSTRACT

A stimulation system delivers stimulation to protect an ischemic region of a body from tissue damage caused by ischemia. The stimulation is delivered to one or more stimulation sites remote from the ischemic region to elicit a physiological effect that protects the ischemic region from the tissue damage caused by ischemia. In one embodiment, the stimulation system delivers cardioprotective stimulation to one or more stimulation sites remote from the heart to protect the heart from injuries associated with cardiac ischemic events. In another embodiment, the stimulation system delivers remote conditioning stimulation to one or more stimulation sites in or on the heart to protect a non-cardiac region from injuries associated with non-cardiac ischemic events.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is related to commonly assigned, U.S. patentapplication Ser. No. 11/220,397, entitled “METHOD AND APPARATUS FORDEVICE CONTROLLED GENE EXPRESSION FOR CARDIAC PROTECTION,” filed on Sep.6, 2005, now U.S. Pat. No. 7,774,057, U.S. patent application Ser. No.11/207,251, entitled “METHOD AND APPARATUS FOR DELIVERING CHRONIC ANDPOST-ISCHEMIA CARDIAC THERAPIES,” filed on Aug. 19, 2005, now U.S. Pat.No. 7,668,594, U.S. patent application Ser. No. 11/129,058, entitled“METHOD AND APPARATUS FOR DELIVERING PACING PULSES USING A CORONARYSTENT,” filed on May 13, 2005, now abandoned, and U.S. patentapplication Ser. No. 11/129,050, entitled “METHOD AND APPARATUS FORCARDIAC PROTECTION PACING,” filed on May 13, 2005, which are herebyincorporated herein by reference in their entirety.

TECHNICAL FIELD

This document relates generally to medical devices and particularly to asystem for protecting the heart from injuries associated with cardiacischemic events by delivering stimulation to one or more sites remotefrom the ischemic region.

BACKGROUND

Ischemia is a condition in which portions of a body are deprived ofadequate oxygen and metabolite removal due to an interruption in bloodsupply caused by an occlusion of a blood vessel. The inadequate oxygensupply and metabolite removal cause tissue injury that may result inimpaired physiological functions of an organ to which the adequate bloodflow is interrupted. One example of ischemia is cardiac ischemia, acondition in which the myocardium is deprived of adequate supply ofblood due to occlusion of a blood vessel such as a coronary artery.

The heart is the center of a person's circulatory system. It includes anelectro-mechanical system performing two major pumping functions. Theleft portions of the heart draw oxygenated blood from the lungs and pumpit to the organs of the body to provide the organs with their metabolicneeds for oxygen. The right portions of the heart draw deoxygenatedblood from the body organs and pump it to the lungs where the blood getsoxygenated. These pumping functions are resulted from contractions ofthe myocardium. In a normal heart, the sinoatrial node, the heart'snatural pacemaker, generates electrical impulses that propagate throughan electrical conduction system to various regions of the heart toexcite the myocardial tissues of these regions. Coordinated delays inthe propagations of the electrical impulses in a normal electricalconduction system cause the various portions of the heart to contract insynchrony to result in efficient pumping functions. A blocked orotherwise abnormal electrical conduction and/or deteriorated myocardialtissue cause dysynchronous contraction of the heart, resulting in poorhemodynamic performance, including a diminished blood supply to theheart and the rest of the body. The condition where the heart fails topump enough blood to meet the body's metabolic needs is known as heartfailure.

Myocardial infarction (MI) is the necrosis of portions of the myocardialtissue resulted from cardiac ischemia, a condition in which themyocardium is deprived of adequate oxygen and metabolite removal due toan interruption in blood supply caused by an occlusion of a blood vesselsuch as a coronary artery. The necrotic tissue, known as infarctedtissue, loses the contractile properties of the normal, healthymyocardial tissue. Consequently, the overall contractility of themyocardium is weakened, resulting in an impaired hemodynamicperformance. Following an MI, cardiac remodeling starts with expansionof the region of infarcted tissue and progresses to a chronic, globalexpansion in the size and change in the shape of the entire leftventricle. The consequences include a further impaired hemodynamicperformance and a significantly increased risk of developing heartfailure, as well as a risk of suffering recurrent MI.

Therefore, there is a need to protect tissue from ischemic damage,including the need to protect the heart from injuries associated withcardiac ischemic events.

SUMMARY

A stimulation system delivers stimulation to protect an ischemic regionof a body from tissue damage caused by ischemia. The stimulation isdelivered to one or more stimulation sites remote from the ischemicregion to elicit a physiological effect that protects the ischemicregion from the tissue damage caused by ischemia.

In one embodiment, a cardioprotective stimulation system includes atleast one stimulation output device coupled to an implantable medicaldevice. The stimulation output device is configured for placement in astimulation site remote from the heart. The implantable medical deviceincludes a cardioprotective stimulation module and a cardioprotectivestimulation controller. The cardioprotective stimulation module deliversone or more non-cardiac stimuli to the stimulation site through thestimulation output device. The one or more non-cardiac stimuli arecapable of eliciting a cardioprotective effect against cardiac ischemiawithout causing myocardial contraction. The cardioprotective stimulationcontroller includes a stimulation initiator and a stimulation timer. Thestimulation initiator produces cardioprotective stimulation signals. Inresponse to each of the cardioprotective stimulation signals, thestimulation timer times a cardioprotective stimulation sequence. Thecardioprotective stimulation sequence includes alternating stimulationand non-stimulation periods. The stimulation periods each have astimulation duration during which the one or more non-cardiac stimuliare delivered. The non-stimulation periods each have a non-stimulationduration during which no non-cardiac stimulus is delivered.

In one embodiment, a method for operating an implantable medical devicefor cardioprotection against cardiac ischemia is provided. Acardioprotective stimulation signal is received. In response to thecardioprotective stimulation signal, a cardioprotective stimulationsequence is timed. The cardioprotective stimulation sequence includesalternating stimulation and non-stimulation periods. The stimulationperiods each have a stimulation duration during which one or morenon-cardiac stimuli are delivered. The non-stimulation periods each havea non-stimulation duration during which no non-cardiac stimulus isdelivered. The one or more non-cardiac stimuli are delivered from theimplantable medical device to at least one stimulation site remote fromthe heart during each of the stimulation period. The one or morenon-cardiac stimuli are capable of eliciting a cardioprotective effectagainst cardiac ischemia without causing myocardial contraction.

In one embodiment, an implantable medical device includes a cardiacelectrical stimulation circuit and a cardiac stimulation controller. Thecardiac electrical stimulation circuit delivers pacing pulses to acardiac location. The cardiac stimulation controller initiates and timesa remote conditioning stimulation sequence in response to a therapyinitiation event. The remote conditioning stimulation sequence includesalternating pacing and non-pacing periods. The pacing pulses aredelivered during each of the pacing periods at a pacing rate that issufficiently high to elicit a physiological effect that protects anon-cardiac ischemic region from ischemic tissue damage by inducingcardiac ischemia. No pacing pulse is delivered during the non-pacingperiods.

In one embodiment, a method for operating an implantable medical deviceto perform remote conditioning to protect a non-cardiac ischemic regionfrom ischemic damage by stimulating the heart is provided. A remoteconditioning stimulation sequence is initiated in response to a therapyinitiation event. The remote conditioning stimulation sequence includesalternating pacing and non-pacing periods. Cardiac pacing pulses aredelivered during each of the pacing periods at a pacing rate that issufficiently high to elicit a physiological effect that protects thenon-cardiac ischemic region from ischemic tissue damage by inducingcardiac ischemia.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects of the invention will be apparent to persons skilled in the artupon reading and understanding the following detailed description andviewing the drawings that form a part thereof. The scope of the presentinvention is defined by the appended claims and their legal equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings illustrate generally, by way of example, variousembodiments discussed in the present document. The drawings are forillustrative purposes only and may not be to scale.

FIG. 1 is an illustration of an embodiment of a stimulation system andportions of an environment in which the stimulation system is used.

FIG. 2 is a block diagram illustrating an embodiment of portions of acircuit of a cardioprotective stimulation system.

FIG. 3 is a block diagram illustrating a specific embodiment of portionsof the circuit of the cardioprotective stimulation system.

FIG. 4 is a block diagram illustrating an embodiment of acardioprotective stimulation module of the cardioprotective stimulationsystem.

FIG. 5 is an illustration of a cardiac rhythm management (CRM) systemincluding the cardioprotective stimulation system and portions of anenvironment in which the CRM system is used.

FIG. 6 is a block diagram illustrating an embodiment of portions ofcircuits of the CRM system.

FIG. 7 is a block diagram illustrating an embodiment of portions of acircuit of an external system of the CRM system.

FIG. 8 is a block diagram illustrating an embodiment of the externalsystem.

FIG. 9 is a block diagram illustrating an embodiment of stimulationelectrodes for cardioprotective stimulation.

FIG. 10 is a flow chart illustrating an embodiment of a method forcardioprotective stimulation.

FIG. 11 is a flow chart illustrating a specific embodiment of the methodfor cardioprotective stimulation.

FIG. 12 is an illustration of an embodiment of timing ofcardioprotective stimulation sequences.

FIG. 13 is an illustration of an embodiment of timing of stimulation andnon-stimulation periods during a cardioprotective stimulation sequence.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings which form a part hereof, and in which is shown byway of illustration specific embodiments in which the invention may bepracticed. These embodiments are described in sufficient detail toenable those skilled in the art to practice the invention, and it is tobe understood that the embodiments may be combined, or that otherembodiments may be utilized and that structural, logical and electricalchanges may be made without departing from the spirit and scope of thepresent invention. References to “an”, “one”, or “various” embodimentsin this disclosure are not necessarily to the same embodiment, and suchreferences contemplate more than one embodiment. The following detaileddescription provides examples, and the scope of the present invention isdefined by the appended claims and their legal equivalents.

This document discusses a stimulation system providing for remoteconditioning that elicits physiological protective effect againstischemic damage. The stimulation system protects an ischemic region of abody from tissue damage caused by ischemia by delivering stimulation toone or more stimulation sites in or on the body but remote from theischemic region.

One example of a stimulation system according to the present subjectmatter includes an implantable medical device that deliverscardioprotective stimulation (also known as cardiac protectionstimulation) to protect the heart from injuries associated with cardiacischemic events, including MI. Cardioprotective therapies delivered to aheart, such as ischemic postconditioning, ischemic preconditioning,pacing postconditioning, and pacing preconditioning, have showncardioprotective effects by reducing myocardial tissue damage caused byischemic events, including MI. Ischemic postconditioning protects themyocardium by inducing brief periods of ischemia after an ischemic eventis detected. Ischemic preconditioning is a prophylactic therapy thatprotects the myocardium from an anticipated or predicted ischemic eventby inducing brief periods of ischemia before the occurrence of theischemic event. Pacing postconditioning protects the myocardium bydelivering brief periods of a pacing therapy to the heart after anischemic event is detected. Pacing preconditioning is a prophylactictherapy that protects the myocardium from an anticipated or predictedischemic event by brief periods of a pacing therapy to the heart beforethe occurrence of such ischemic event. One specific example of pacingpreconditioning is to deliver brief periods of pacing therapy to protectthe myocardium from potentially recurring ischemic events after thepacing postconditioning has been delivered. In additions to suchcardioprotective therapies delivered to a heart, ischemicpreconditioning therapy delivered to a region in the body at a distancefrom the heart have also shown cardioprotective effects against cardiacischemia.

According to the present subject matter, the cardioprotectivestimulation includes delivery of one or more stimuli to one or morestimulation sites in the body of a patient to elicit a cardioprotectiveeffect against cardiac ischemia. The one or more stimulation sites areremote from the patient's heart and/or in the patient's heart but remotefrom any cardiac ischemic region. The one or more stimuli may create aphysiologic stress in the one or more stimulation sites, and thephysiologic stress triggers an intrinsic myocardial protective mechanismagainst ischemic damage to the myocardial tissue. In one embodiment, theimplantable medical device detects cardiac ischemic events. In responseto the detection of a cardiac ischemic event, a cardioprotectivestimulation sequence is initiated to protect the heart from ischemicdamage caused by the detected cardiac ischemic event. Then, additionalcardioprotective stimulation sequences are initiated to protect theheart from ischemic damage caused by potentially recurrent cardiacischemic events. In another embodiment, the implantable medical devicereceives a cardioprotective stimulation command. In response, acardioprotective stimulation sequence is initiated. The cardioprotectivestimulation command is issued by a physician or other caregiver or thepatient in response to a cardiac ischemic event that has occurred or adiagnosis classifying the patient as having a high risk of cardiacischemia or MI. Examples of indications of high risk of cardiac ischemiaor MI include coronary artery disease (CAD), previous MI, unstableangina, and vulnerable plaque. In one embodiment, each cardioprotectivestimulation sequence includes alternating stimulation andnon-stimulation periods. The stimulation periods each have a stimulationduration during which one or more stimuli are delivered. Thenon-stimulation periods each have a non-stimulation duration duringwhich no stimulus is delivered. In other words, the cardioprotectivestimulation sequence includes intermittent stimulation over apredetermined duration. The stimulation is delivered in any form ofenergy that is capable eliciting a cardioprotective effect againstischemic damage to the myocardial tissue. Examples of such stimulationinclude electrical stimulation, mechanical stimulation, chemicalstimulation, biologic stimulation, optical stimulation, thermalstimulation, and acoustic stimulation.

While implantable medical devices are specifically discussed in thisdocument as examples of a device that delivers cardioprotectivestimulation, the present subject matter is not limited to implantablemedical devices. In general, the cardioprotective stimulation accordingto the present subject matter can be delivered by any implantable ornon-implantable medical devices that are capable of delivering any formof stimulation that elicits cardioprotective effect against cardiacischemia from any location in a body remote from the cardiac ischemicregion(s).

While cardioprotective stimulation is specifically discussed in thisdocument as an example of remote conditioning for tissue protectionagainst ischemia, the present subject matter is not limited tocardioprotective stimulation. Other examples of a stimulation systemaccording to the present subject matter include stimulation devices thatdeliver stimulation to protect non-cardiac tissue or organ againstischemic damage. Specific examples of such stimulation devices include astimulator for protection against tissue damage caused by ischemicstroke, a stimulator for protection against damage to a kidney caused byischemic renal failure, a stimulator for protection against neuraldamage caused by ischemia in the central nervous system, and astimulator for protection against muscular damage caused by ischemia inskeletal muscle. In one embodiment, the remote conditioning for tissueprotection against ischemia is performed by electrically stimulating theheart to elicit protective effects in tissue remote from the heart. Thisallows a cardiac stimulation device such as an implantable pacemaker todeliver a therapy that protects a non-cardiac organ from ischemicdamage. For example, pacing pulses may be delivered to the heart at arate that is sufficiently high to induce transient cardiac ischemia.Through the autonomic nervous system, the transient cardiac ischemiaelicits protective effects against ischemic injury in other organsinnervated by the autonomic nervous system. In general, the stimulationaccording to the present subject matter can be delivered by anyimplantable or non-implantable medical devices that are capable ofdelivering any form of stimulation that elicits physiological protectiveeffect against ischemic damage from any location in a body remote fromthe region(s) wherein ischemia occurs in the body.

FIG. 1 is an illustration of an embodiment of a stimulation system 100and portions of an environment in which system 100 is used. In theembodiment illustrated in FIG. 1, system 100 is a cardioprotectivestimulation system. In various other embodiments, system 100 includes astimulation system that delivers stimulation to one or more stimulationsites remote from an injured region to protect the injured region fromischemic damage. As illustrated in FIG. 1, system 100 includes animplantable medical device 110 and a stimulation output device 112. Asillustrated in FIG. 1, system 100 is implanted in a patient's body 102having a heart 101. Heart 101 has an ischemic region 103 that includesischemic tissue resulted from a cardiac ischemic event, such as an acuteMI.

Stimulation output device 112 is placed in a location in body 102 thatis remote from ischemic region 103. Implantable medical device 110includes an implantable housing that contains a stimulation module thatdelivers one or more stimuli through stimulation output device 112. Theone or more stimuli elicit a cardioprotective effect that reducesischemic damage in and around ischemic region 103. Stimulation outputdevice 112 is connected to implantable medical device 110 directly orthrough a lead that allow transmission of the one or more stimuli.

In one embodiment, as illustrated in FIG. 1, stimulation device outputdevice 112 is placed in a location in body 102 that is remote from heart101. The one or more stimuli that elicit the cardioprotective effect areone or more non-cardiac stimuli. Implantable medical device 110 includesa non-cardiac stimulation module that delivers the one or morenon-cardiac stimuli through stimulation output device 112. The one ormore non-cardiac stimuli elicit a cardioprotective effect that reducesischemic damage in and around ischemic region 103 without causingmyocardial contraction in heart 101. That is, the one or morenon-cardiac stimuli are delivered to a stimulation site remote from theheart and do not activate the heart as pacing, cardioversion, ordefibrillation does.

In one embodiment, implantable medical device 110 is a dedicatedcardioprotective stimulator that delivers the one or more stimulieliciting the cardioprotective effect. In various other embodiments,implantable medical device 110 is an implantable device including thefunctionality of cardioprotective stimulation. Examples of such animplantable device include a CRM device (such as a pacemaker, acardioverter/defibrillator, and a cardiac resynchronization therapydevice), a neural stimulator that provides for sympathetic and/orparasympathetic neural stimulation, a muscular stimulator, aneuromuscular stimulator, a drug delivery device, a biologic therapydevice, and a physiological monitor.

In various embodiments in which system 100 is used to protectnon-cardiac tissue or organs against ischemic damage, implantablemedical device 110 includes one or more of a stimulator that protectsneural or other tissue from ischemic stroke, a stimulator that protectskidney(s) from ischemic renal failure, a stimulator that protects neuraltissue from ischemia in the central nervous system, and a stimulatorthat protects muscular tissue from ischemia in skeletal muscle. In oneembodiment, implantable medical device 110 includes a cardiacstimulation device that delivers one or more therapies to protectnon-cardiac tissue or organs against ischemic damage by deliveringelectrical stimulation pulses to the heart. In a specific embodiment,the cardiac stimulation device is a CRM device that is capable ofdelivering cardiac therapies, cardioprotective therapies, and/or remoteconditioning therapies. For example, the cardiac stimulation devicedelivers cardiac therapies such as pacing therapies on a long-termbasis. In response to the detection of a cardiac ischemic event, thecardiac stimulation device delivers a cardioprotective therapy. Inresponse to the detection of an ischemic event in a non-cardiac locationof the body, the cardiac stimulation device delivers a remoteconditioning therapy by eliciting protective effects through theautonomic nervous system.

FIG. 2 is a block diagram illustrating an embodiment of portions of acircuit of a cardioprotective stimulation system 200. System 200 is aspecific embodiment of system 100 and includes stimulation output device112 and an implantable medical device 210.

Stimulation output device 112 provides for an interface betweenimplantable medical device 210 and tissue at one or more stimulationsites in body 102. The interface allows delivery of cardioprotectivestimulation into the tissue. Stimulation output device 112 is configuredfor placement in the one or more stimulation sites, which are locationsin body 102 that are remote from ischemic region 103. Stimulation outputdevice 112 is connected to implantable medical device 210. In oneembodiment, stimulation output device 112 is connected to implantablemedical device 210 through a lead. In another embodiment, stimulationoutput device 112 is physically attached to implantable medical device210, such as incorporated onto the housing of implantable medical device210. In another embodiment, stimulation output device 112 is part ofimplantable medical device 210, such as a portion of implantable medicaldevice 210 that provides for an interface through which cardioprotectivestimulation is delivered into tissue.

Implantable medical device 210 is a specific embodiment of implantablemedical device 110 and includes a cardioprotective stimulation module214 and a cardioprotective stimulation controller 216. Cardioprotectivestimulation module 214 delivers one or more stimuli into tissue at theone or more stimulation sites through stimulation output device 112. Theone or more stimuli are capable of eliciting a cardioprotective effectagainst cardiac ischemia. Examples of such one or more stimuli includesone or more stimuli creating a physiologic stress at the one or morestimulation sites, one or more stimuli creating a local ischemiccondition at the one or more stimulation sites, and one or more stimulicausing a release of one or more cardioprotective paracrine factors.Cardioprotective stimulation controller 216 controls the delivery of theone or more stimuli and includes a stimulation initiator 218 and astimulation timer 220. Stimulation initiator 218 producescardioprotective stimulation signals each initiating a cardioprotectivestimulation sequence. In various embodiments, stimulation initiator 218produces cardioprotective stimulation signals in response to apredetermined event sensed by implantable medical device 210 or apredetermined command received by implantable medical device 210.Stimulation timer 220 times the cardioprotective stimulation sequence.The cardioprotective stimulation sequence includes alternatingstimulation and non-stimulation periods. Each stimulation period has astimulation duration during which the one or more stimuli are deliveredto the one or more stimulation sites. Each non-stimulation period has anon-stimulation duration during which none of the one or more stimuli isdelivered to the one or more stimulation sites.

FIG. 3 is a block diagram illustrating a specific embodiment of portionsof the circuit of a cardioprotective stimulation system 300, which is aspecific embodiment of cardioprotective stimulation system 200.Cardioprotective stimulation system 300 includes stimulation outputdevice 212, an implantable medical device 310, and a physiologicalstress sensor 322.

Implantable medical device 310 is a specific embodiment of implantablemedical device 210 and includes cardioprotective stimulation module 214and a cardioprotective stimulation controller 316. Cardioprotectivestimulation controller 316 is a specific embodiment of cardioprotectivestimulation controller 216 and includes a stimulation initiator 318 anda stimulation timer 320. Stimulation initiator 318 is a specificembodiment of stimulation initiator 218 and produces thecardioprotective stimulation signals in response to a detected cardiacischemic event and/or a command sent by a physician or other caregiveror the patient.

In the embodiment illustrated in FIG. 3, stimulation initiator 318includes an ischemia detector 324 and a stimulation command detector326. In various embodiments, stimulation initiator 318 includes any oneor both of ischemia detector 324 and stimulation command detector 326.

Ischemia detector 324 includes an ischemia analyzer running an automaticischemia detection algorithm to detect cardiac ischemic events from oneor more signals sensed from body 102. In one embodiment, ischemiadetector 324 produces an ischemia alert signal indicative of thedetection of each cardiac ischemic event. The ischemia alert signal iscommunicated to a physician or other caregiver or the patient as analarm signal and/or a warning message. In one embodiment, implantablemedical device 310 includes a speaker to produce an audible alarm signaland/or warning message. In another embodiment, implantable medicaldevice 310 transmits the ischemia alert signal to an external system.The external system produces the alarm signal and/or warning message tocommunicate to the physician or other caregiver or the patient.

In one embodiment, ischemia detector 324 detects the cardiac ischemicevents from one or more cardiac signals. Ischemia detector 324 includesor communicates to a cardiac sensing circuit that senses the one or morecardiac signals. In a specific example, cardiac signals are sensed usinga wearable vest including embedded electrodes configured to sensesurface biopotential signals indicative of cardiac activities. Thesensed surface biopotential signals are transmitted to implantablemedical device 310 via telemetry. In another specific embodiment,ischemia detector 324 detects the cardiac ischemic events from one ormore wireless electrocardiogram (ECG) signals. A wireless ECG is asignal approximating the surface ECG and is acquired without usingsurface (skin contact) electrodes. An example of a circuit for sensingthe wireless ECG is discussed in U.S. patent application Ser. No.10/795,126, entitled “WIRELESS ECG IN IMPLANTABLE DEVICES,” filed onMar. 5, 2004, assigned to Cardiac Pacemakers, Inc., which isincorporated herein by reference in its entirety. An example of awireless ECG-based ischemia detector is discussed in U.S. patentapplication Ser. No. 11/079,744, entitled “CARDIAC ACTIVATION SEQUENCEMONITORING FOR ISCHEMIA DETECTION,” filed on Mar. 14, 2005, assigned toCardiac Pacemakers, Inc., which is incorporated herein by reference inits entirety. In another embodiment, ischemia detector 324 detects thecardiac ischemic events from one or more electrogram signals. Examplesof an electrogram-based ischemia detector are discussed in U.S. Pat. No.6,108, 577, entitled, “METHOD AND APPARATUS FOR DETECTING CHANGES INELECTROCARDIOGRAM SIGNALS,” and U.S. patent application Ser. No.09/962,852, entitled “EVOKED RESPONSE SENSING FOR ISCHEMIA DETECTION,”filed on Sep. 25, 2001, both assigned to Cardiac Pacemakers, Inc., whichare incorporated herein by reference in their entirety.

In another embodiment, ischemia detector 324 detects the cardiacischemic events from one or more impedance signals. Ischemia detector324 includes or communicates to an impedance sensing circuit that sensesthe one or more impedance signals each indicative of a cardiac impedanceor a transthoracic impedance. Ischemia detector 324 includes anelectrical impedance based sensor using a low carrier frequency todetect the cardiac ischemic events from an electrical impedance signal.Tissue electrical impedance has been shown to increase significantlyduring ischemia and decrease significantly after ischemia, as discussedin Dzwonczyk, et al. IEEE Trans. Biomed. Eng., 99(12): 2206-09 (2004).Ischemia detector 324 senses low frequency electrical impedance signalbetween electrodes interposed in the heart, and detects the ischemia asabrupt changes in impedance (such as abrupt increases in value).

In another embodiment, ischemia detector 324 detects the cardiacischemic events from one or more signals indicative of heart sounds.Ischemia detector 324 includes or communicates to a heart sound sensingcircuit. The heart sound sensing circuit senses the one or more signalsindicative of heart sounds using one or more sensors such as implantableaccelerometers and/or microphones. Ischemia detector 324 detects thecardiac ischemic event by detecting predetermined type heart sounds,predetermined type heart sound components, predetermined typemorphological characteristics of heart sounds, or other characteristicsof heart sounds indicative of ischemia.

In another embodiment, ischemia detector 324 detects the cardiacischemic events from one or more pressure signals. Ischemia detector 324includes or communicates to a pressure sensing circuit coupled to one ormore pressure sensors. In a specific embodiment, the pressure sensor isan implantable pressure sensor sensing a signal indicative of anintracardiac or intravascular pressure whose characteristics areindicative of ischemia.

In another embodiment, ischemia detector 324 detects the cardiacischemic event from one or more acceleration signals each indicative ofregional cardiac wall motion. Ischemia detector 324 includes orcommunicates to cardiac motion sensing circuit coupled to one or moreaccelerometers each incorporated into a portion of a lead positioned onor in the heart. The ischemia detector detects ischemia as an abruptdecrease in the amplitude of local cardiac accelerations.

In another embodiment, ischemia detector 324 detects the cardiacischemic event from a heart rate variability (HRV) signal indicative ofHRV. Ischemia detector 324 includes or communicates to an HRV sensingcircuit that senses the HRV and produces the HRV signal, which isrepresentative of an HRV parameter. HRV is the beat-to-beat variance incardiac cycle length over a period of time. The HRV parameter includesany parameter being a measure of the HRV, including any qualitativeexpression of the beat-to-beat variance in cardiac cycle length over aperiod of time. In a specific embodiment, the HRV parameter includes theratio of Low-Frequency (LF) HRV to High-Frequency (HF) HRV (LF/HFratio). The LF HRV includes components of the HRV having frequenciesbetween about 0.04 Hz and 0.15 Hz. The HF HRV includes components of theHRV having frequencies between about 0.15 Hz and 0.40 Hz. Ischemiadetector 324 detects ischemia when the LF/HF ratio exceeds apredetermined threshold. An example of an LF/HF ratio-based ischemiadetector is discussed in U.S. patent application Ser. No. 10/669,168,entitled “METHOD FOR ISCHEMIA DETECTION BY IMPLANTABLE CARDIAC DEVICE,”filed on Sep. 23, 2003, assigned to Cardiac Pacemakers, Inc., which isincorporated herein by reference in its entirety.

In one embodiment, in response to a detection of the cardiac ischemicevent, stimulation initiator 318 produces a postconditioning signal. Thepostconditioning signal is a cardioprotective stimulation signal thatstarts a postconditioning stimulation sequence. The postconditioningstimulation sequence is a cardioprotective stimulation sequence thatfollows the occurrence of a cardiac ischemic event to reduce the tissuedamage associated with that cardiac ischemic event. In one embodiment,stimulation initiator 318 produces the postconditioning signal when theend of the cardiac ischemic event is detected. In a specific embodiment,the end of the cardiac ischemic event is detected when the cardiacischemic event is no longer detected by ischemia detector 324. Inanother embodiment, stimulation initiator 318 produces thepostconditioning signal when a post-ischemia time interval expires. Thepost-ischemia time interval starts when the end of the cardiac ischemicevent is detected and is up to approximately 10 minutes, withapproximately 30 seconds being a specific example. In one embodiment,the post-ischemia time interval is chosen such that the postconditioningstimulation sequence is initiated after the reperfusion phase followingthe cardiac ischemic event has started.

In a further embodiment, in addition to producing the postconditioningsignal, stimulation initiator 318 produces a plurality ofpreconditioning signals in response to the detection of the cardiacischemic event. Each preconditioning signal is a cardioprotectivestimulation signal that starts a prophylactic preconditioningstimulation sequence. The preconditioning stimulation sequence is acardioprotective stimulation sequence that follows the occurrence of thecardiac ischemic event to reduce potential tissue damage associated withan anticipated recurring cardiac ischemic event. Stimulation initiator318 produces the plurality of preconditioning signals after the end ofthe cardiac ischemic event is detected and the postconditioningstimulation sequence is completed. In one embodiment, stimulationinitiator 318 produces the plurality of preconditioning signalsaccording to a programmed preconditioning schedule. In a specificembodiment, stimulation initiator 318 produces the plurality ofpreconditioning signals on a periodic basis using a predeterminedperiod. The predetermined period is in a range of approximately 24 hoursto 72 hours, with approximately 48 hours being a specific example.

Stimulation command detector 326 detects a cardioprotective stimulationcommand. In one embodiment, the cardioprotective stimulation command isin a form of a predetermined simple signal such as the presence of amagnetic field. The cardioprotective stimulation command triggers one ormore cardioprotective stimulation sequences that have been programmedinto stimulation timer 320. In another embodiment, the cardioprotectivestimulation command includes a code. In a specific embodiment, the codespecifies programmable parameters controlling timing and or intensity ofone or more cardioprotective stimulation sequences.

In one embodiment, in response to a detection of the cardioprotectivestimulation command, stimulation initiator 318 produces acardioprotective stimulation signal. In a specific embodiment,stimulation initiator 318 produces a postconditioning signal and aplurality of preconditioning signals in response to the detection of thecardioprotective stimulation command. The postconditioning signal isproduced when the cardioprotective stimulation command is detected. Theplurality of preconditioning signals are produced according to apredetermined schedule, such as on a periodic basis using apredetermined period in a range of approximately 24 hours to 72 hours,with approximately 48 hours being a specific example. In anotherspecific embodiment, stimulation initiator 318 produces apostconditioning signal when the detected cardioprotective stimulationcommand is a postconditioning command and produces a preconditioningsignal when the detected cardioprotective stimulation command is apreconditioning command.

In one embodiment, stimulation initiator 318 produces a postconditioningsignal in response to the detection of any one of the cardiac ischemicevent or the cardioprotective stimulation command. If a cardiac ischemicevent and a cardioprotective stimulation command are detected within apredetermined period of time, they are deemed to be associated with thesame cardiac ischemic event by stimulation initiator 318.

Stimulation timer 320 is a specific embodiment of stimulation timer 220and includes a postconditioning timer 328 and a preconditioning timer330. Postconditioning timer 328 receives the postconditioning signalfrom stimulation initiator 318 and times a postconditioning stimulationsequence when the postconditioning signal is received. Thepostconditioning stimulation sequence includes alternatingpostconditioning stimulation and non-stimulation periods. Thepostconditioning stimulation periods each have a postconditioningstimulation duration during which one or more stimuli are delivered. Thepostconditioning non-stimulation periods each have a postconditioningnon-stimulation duration during which no stimulus is delivered.Preconditioning timer 330 receives each of the preconditioning signalsand times a preconditioning stimulation sequence when one of thepostconditioning signals is received from stimulation initiator 318. Thepreconditioning stimulation sequence includes alternatingpreconditioning stimulation and non-stimulation periods. Thepreconditioning stimulation periods each have a preconditioningstimulation duration during which one or more stimuli are delivered. Thepreconditioning non-stimulation periods each have a preconditioningnon-stimulation duration during which no stimulus is delivered.

Cardioprotective stimulation parameters including the postconditioningstimulation sequence duration, the postconditioning stimulationduration, the postconditioning non-stimulation duration, thepreconditioning stimulation sequence duration, the preconditioningstimulation duration, and the preconditioning non-stimulation durationare dependent on the type of the one or more stimuli and the location ofthe one or more stimulation sites in a body. In one embodiment, thesecardioprotective stimulation parameters are statistically determinedbased on clinical studies. In one embodiment, these cardioprotectivestimulation parameters are programmable for each individual patient. Thecardioprotective stimulation parameters also include stimulationmagnitude parameters controlling the intensity of the one or morestimuli. These stimulation magnitude parameters are programmable foreach individual patient and are programmed to values that produce thedesirable effect while avoiding over-stimulation or unintended effectsof stimulation.

In a specific embodiment, electrical stimulation pulses are delivered toskeletal muscles in the pectoral area for cardioprotective effectsagainst cardiac ischemia. The electrical stimulation pulses aresubstantially similar to cardiac pacing pulses. The electricalstimulation pulses are each controlled by a pulse amplitude and pulseduration. The postconditioning stimulation sequence has apostconditioning stimulation sequence duration in a range ofapproximately 30 seconds to 1 hour, with approximately 10 minutes beinga specific example. The postconditioning stimulation duration is in arange of approximately 5 seconds to 1 minute, with approximately 30seconds being a specific example. The postconditioning non-stimulationduration is in a range of approximately 5 seconds to 1 minute, withapproximately 30 seconds being a specific example. The preconditioningstimulation sequences each have a preconditioning stimulation sequenceduration in a range of approximately 10 minutes to 72 hours, withapproximately 40 minutes being a specific example. The preconditioningstimulation duration is in a range of approximately 1 minute to 1 hour,with approximately 5 minutes being a specific example. Thepreconditioning non-stimulation duration is in a range of approximately1 minute to 1 hour, with approximately 5 minutes being a specificexample.

Physiological stress sensor 322 senses a stress-indicating signalindicative of a level of the physiological stress at the one or morestimulation sites. The stress-indicating signal serves as a quantitativeindication of the cardioprotective effect resulted from thecardioprotective stimulation. In one embodiment, cardioprotectivestimulation controller 316 controls the delivery of the one or morestimuli using the stress-indicating signal. In a specific embodiment,cardioprotective stimulation controller 316 adjusts the cardioprotectivestimulation parameters using the stress-indicating signal. In oneembodiment, physiological stress sensor 322 is connected to implantablemedical device 310 using a wired link or a wireless telemetry link. Inanother embodiment, physiological stress sensor 322 is part ofimplantable medical device 310 and contained in the implantable housing.

In one embodiment, physiological stress sensor 322 includes a cardiacsensing circuit to sense an electrogram, and the level of thephysiological stress is measured by S-T segment elevation in theelectrogram. In another embodiment, physiological stress sensor 322includes a strain gauge that measures the degree of muscular contractioncause by the cardioprotective stimulation. In another embodiment,physiological stress sensor 322 includes a chemical sensor, such as a pHsensor, to sense a degree of chemical reaction to the cardioprotectivestimulation.

In another embodiment, physiological stress sensor 322 includes one ormore exertion level sensors each sensing an exertion level being anindication or measure of a physiological response to thecardioprotective stimulation. Examples of the exertion level sensorinclude a chemical sensor that senses pH value, an oximeter orplethysmography sensor that senses a signal oximetry or plethysmographysignal indicative of blood oxygen saturation, an impedance sensor thatsenses a respiratory signal indicative of minute ventilation sensor orrespiratory rate, an time interval detector that detects one or morepredetermined type cardiac intervals from one or more electrogramsignals, and a temperature sensor that senses body temperature, bloodtemperature, and/or myocardial temperature. In one embodiment,implantable medical device 310 provides rate-adaptive pacing that usesan exertion level sensor for pacing control. This exertion level sensoris also used as physiological stress sensor 322 for cardioprotectivestimulation control.

FIG. 4 is a block diagram illustrating an embodiment of acardioprotective stimulation module 414, which represents a specificembodiment of cardioprotective stimulation module 214. In variousembodiments, cardioprotective stimulation module 214 includes any one ormore illustrated elements of cardioprotective stimulation module 414 aswell as other elements that are also capable of eliciting thecardioprotective effects by delivering stimulation to the one or morestimulation sites remote from the ischemic region.

As illustrated in FIG. 4, cardioprotective stimulation module 414includes an electrical stimulation device 440 that delivers one or moreelectrical stimuli, a mechanical stimulation device 441 that deliversone or more mechanical stimuli, a chemical stimulation device 442 thatdelivers one or more chemical stimuli, a biological stimulation device443 that delivers one or more biologic stimuli, an optical stimulationdevice 444 that delivers one or more optical stimuli, a thermalstimulation device 445 that delivers one or more thermal stimuli, and anacoustic stimulation device 446 that delivers one or more acousticstimuli.

Electrical stimulation device 440 includes an electrical stimulationcircuit to deliver electrical stimulation pulses. Examples of theelectrical stimulation circuit include cardiac pacing circuit,neurostimulation circuit, neuromuscular stimulation circuit, muscularstimulation circuit, and other electrical stimulation circuit capable ofactivating portions of a body using electrical energy.

Mechanical stimulation device 441 includes a mechanical stress-creatingdevice to create a stress in tissue. Examples of such a mechanicalstress-creating device include a device that create a local ischemiccondition and a device that creates compression, stretch, or other formsof physical deformation of tissue.

Chemical stimulation device 442 includes a drug delivery device todeliver one or more chemical agents. Examples of such one or morechemical agents include lactic acid to cause early muscle fatigue andother mild acids or bases to alter local pH value.

Biological stimulation device 443 includes a biological agent deliverydevice to deliver one or more biological agents and/or a gene regulatorydevice to deliver a gene regulatory signal controlling a geneexpression. In one embodiment, the gene regulatory signal controls aregulatable transcriptional element (such as a promoter) of a naturallyexisting gene. Examples of the gene regulatory device include a lightemitter and a heat emitter. In another embodiment, the gene regulatorysignal controls a regulatable transcriptional element (such as apromoter) of an artificially introduced gene. The gene regulatory deviceincludes a device that emits any form of energy that regulates thetranscriptional element.

Optical stimulation device 444 includes a light emitter to emit a light.In one specific embodiment, the light is a visible light having awavelength in a range of approximately 390 nanometers to 780 nanometers,with a blue light having a wavelength of approximately 470 nanometersbeing a specific example. In one embodiment, the light elicits thecardioprotective effect by controlling a gene expression as discussedabove with respect to biological stimulation device 443 (i.e., in thisembodiment, optical stimulation device 444 represents a specificembodiment of biological stimulation device 443).

Thermal stimulation device 445 includes a thermal emitter to emit alow-intensity electromagnetic wave that rises local tissue temperatureat the one or more stimulation sites. In a specific embodiment, theelectromagnetic wave has a frequency within the radio frequency (RF) ormicrowave range. In one embodiment, the rise of temperature elicits thecardioprotective effect by controlling a gene expression as discussedabove with respect to biological stimulation device 443 (i.e., in thisembodiment, thermal stimulation device 445 represents a specificembodiment of biological stimulation device 443).

Acoustic stimulation device 446 includes an acoustic transducer totransmit an acoustic signal. In one specific embodiment, the acousticsignal is an ultrasonic signal having a wavelength in a range ofapproximately 1 megahertz to 20 megahertz, with approximately 4megahertz being a specific example. In one embodiment, the acousticsignal elicits the cardioprotective effect by controlling a geneexpression as discussed above with respect to biological stimulationdevice 443 (i.e., in this embodiment, acoustic signal stimulation device446 represents a specific embodiment of biological stimulation device443).

In various embodiments in which system 100 is used to protectnon-cardiac tissue or organs against ischemic damage, system 100includes a structure similar to the cardioprotective stimulation systemdiscussed above, except that ischemia detector 324 detects a non-cardiacischemic event, and stimulation timer 320 times the delivery ofstimulation according to a timing suitable for the specific stimulationsite(s). In various embodiments, system 100, 200, or 300 as discussedabove are modified for protecting non-cardiac regions from non-cardiacischemic damage, with ischemia detector 324 adapted to detect aspecified type of ischemia and stimulation timer 320 adapted to time adelivery stimulation to one or more specified stimulation sites remotefrom the region to be protected.

FIG. 5 is an illustration of a CRM system 500 and portions of anenvironment in which CRM system 500 is used. CRM system 500 includes animplantable medical device 510, an external system 550, and a telemetrylink 552 providing for communication between implantable medical device510 and external system 550. Implantable medical device 510 delivers oneor more cardiac electrical therapies to heart 101 through a lead system508 and a cardioprotective stimulation therapy to one or morestimulation sites in body 102 through a stimulation output device 512and/or lead system 508. In one embodiment, the one or more stimulationsites are remote from heart 101. In another embodiment, the one or morestimulation sites are within heart 101 but remote from ischemic region103.

In various embodiments, implantable medical device 510 is an implantableCRM device including one or more of a pacemaker, acardioverter/defibrillator, a cardiac resynchronization therapy (CRT)device, a cardiac remodeling control therapy (RCT) device, aneurostimulator, a drug delivery device or a drug delivery controller,and a biological therapy device. In various embodiments, lead system 508includes leads for sensing physiological signals and deliveringstimulation pulses, cardioversion/defibrillation shocks,neurostimulation pulses, pharmaceutical agents, biological agents,and/or other types of energy or substance for treating cardiacdisorders. In one embodiment, lead system 508 includes one or morestimulation-sensing leads each including at least one electrode placedin or on a heart 101 for sensing electrogram and/or deliveringstimulation pulses. In other embodiments, electrodes placed in body 102but away from heart 101 are used to sense physiological signals anddeliver stimulation pulses, cardioversion/defibrillation shocks,neurostimulation pulses, pharmaceutical agents, biological agents,and/or other types of energy or substance for treating cardiacdisorders.

Implantable medical device 510 also includes a cardioprotectivestimulation system that delivers cardioprotective stimulation throughstimulation output device 512. In one embodiment, the cardioprotectivestimulation is an electrical stimulation. Stimulation output device 512includes one or more electrodes incorporated onto the housing ofimplantable medical device 510. In one embodiment, the one or moreelectrodes are in contact with the epimysium of pectoral muscle.Implantable medical device 510 delivers cardiac electrical stimulationpulses such as pacing pulses and cardioversion/defibrillation pulses toheart 101 through lead system 508 and cardioprotective electricalstimulation pulses to pectoral muscle through the one or more electrodeson the housing of implantable medical device 510.

External system 550 allows the physician or other caregiver and/or thepatient to control the operation of implantable medical device 510 andobtain information acquired by implantable medical device 510. In oneembodiment, external system 550 includes a programmer communicating withimplantable medical device 510 bi-directionally via telemetry link 552.In another embodiment, external system 550 includes a handheld devicecommunicating with implantable medical device 510 bi-directionally viatelemetry link 552. The handheld device allows the patient to startcardioprotective stimulation when the patient feels that an ischemicevent has occurred or is going to occur. In another embodiment, externalsystem 550 is a patient management system including an external devicecommunicating with a remote device through a telecommunication network.The external device is within the vicinity of implantable medical device510 and communicates with implantable medical device 510bi-directionally via telemetry link 552. The remote device allows thephysician or other caregiver to monitor and treat a patient from adistant location. The patient management system is further discussedbelow, with reference to FIG. 8.

Telemetry link 552 provides for data transmission from implantablemedical device 510 to external system 550. This includes, for example,transmitting real-time physiological data acquired by implantablemedical device 510, transmitting the ischemia alert signal produced byimplantable medical device 510, extracting physiological data acquiredby and stored in implantable medical device 510, extracting therapyhistory data stored in implantable medical device 510, and extractingdata indicating an operational status of implantable medical device 510(e.g., battery status and lead impedance). Telemetry link 552 alsoprovides for data transmission from external system 550 to implantablemedical device 510. This includes, for example, programming implantablemedical device 510 to acquire physiological data, programmingimplantable medical device 510 to perform at least one self-diagnostictest (such as for a device operational status), and programmingimplantable medical device 550 to deliver at least one therapy.

FIG. 6 is a block diagram illustrating an embodiment of portions ofcircuits of the implantable elements of CRM system 500. The implantableelements include an implantable medical device 610, electrode(s) 512,and lead system 508. Implantable medical device 610 is a specificembodiment of implantable medical device 510 and includes acardioprotective electrical stimulation circuit 614, a cardiacelectrical stimulation circuit 660, an implant controller 662 thatincludes a cardiac stimulation controller 664 and a cardioprotectivestimulation controller 616, and an implant telemetry circuit 654.

Cardioprotective electrical stimulation circuit 614 is a specificembodiment of cardioprotective stimulation module 214 and deliverselectrical stimulation pulses to one or more stimulation sites remotefrom heart 101 through electrode(s) 512 to elicit a cardioprotectiveeffect against ischemia damages. Cardioprotective stimulation controller616 controls the delivery of the electrical stimulation pulses fromcardioprotective electrical stimulation circuit 614. As a specificembodiment of cardioprotective stimulation controller 216,cardioprotective stimulation controller 616 initiates and times one ormore cardioprotective stimulation sequences as discussed above withrespect to cardioprotective stimulation controller 216 and 316.

Cardiac electrical stimulation circuit 660 delivers electricalstimulation pulses, such as pacing pulses andcardioversion/defibrillation pulses, to heart 101 through lead system508. Cardiac stimulation controller 664 controls the delivery of theelectrical stimulation pulses from cardiac electrical stimulationcircuit 660. In various embodiments, cardiac stimulation controller 664controls one or more of cardiac electrical therapies including, but notlimited to, bradycardia pacing therapy, CRT, RCT, anti-tachycardiapacing therapy, and cardioversion/defibrillation therapy. In variousother embodiments, cardiac stimulation controller 664 controls one ormore of remote conditioning therapies by delivering electricalstimulation pulses, such as pacing pulses, to heart 101 to protect anischemic region external to heart 101 from ischemic tissue damage. Inone embodiment, a remote conditioning therapy is delivered by pacingheart 101 at a rate that is high enough to create transient cardiacischemia. Cardiac stimulation controller 664 controls the delivery ofpacing pulses to one or more pacing sites in or on heart 101 at a pacingrate programmed to create transient cardiac ischemia. In one embodiment,cardiac stimulation controller 664 controls the delivery of pacingpulses according to a remote conditioning stimulation sequence thatincludes alternating pacing and non-pacing periods. Each pacing periodhas a pacing duration during which the pacing pulses are delivered. Eachnon-pacing period has a non-pacing duration during which no pacing pulseis delivered. Such a remote conditioning stimulation sequence creates anintermittent ischemic condition in heart 101.

Implant telemetry circuit 654 transmits and receives signals throughtelemetry link 552. In one embodiment, cardioprotective stimulationcontroller 616 includes an ischemia detector that produces an alertsignal when a cardiac ischemic event is detected. Implant telemetrycircuit 654 transmits the alert signal to external system 550, whichinforms the physician or other caregiver and/or the patient that thecardiac ischemic event is detected.

FIG. 7 is a block diagram illustrating an embodiment of portions of acircuit of an external system 750, which is a specific embodiment ofexternal system 550. External system 750 includes an external telemetrycircuit 756, an ischemia alert signal receiver 770, and a user interface772. External telemetry circuit 756 receives and transmits signalsthrough telemetry link 552. Ischemia alert signal receiver 770 receivesthe alert signal transmitted from implantable medical device 610 when acardiac ischemic event is detected. User interface 772 includes a userinput device 774 and a presentation device 776. User input device 774allows programming of implantable medical device 510, including theentry of cardioprotective stimulation commands that initiate one or morecardioprotective stimulation sequences and/or parameters of thecardioprotective stimulation. Presentation device 776 includes a displayscreen. In one embodiment, presentation device 776 further includes aprinter and a speaker. In one embodiment, portions of user input device774 and presentation device 776 are integrated as an interactive screen.Ischemia alert signal receiver 770 receives the ischemia alert signaland, in response, causes presentation device 776 to produce an alarmsignal and/or a warning message for the physician or caregiver and/orthe patient.

In one embodiment, external system 750 includes a programmer for use bythe physician or other caregiver. In another embodiment, external system750 includes a portable device provided to the patient. In anotherembodiment, external system 750 is a patient management system that isdiscussed below with reference to FIG. 8.

FIG. 8 is a block diagram illustrating an embodiment of an externalsystem 850, which is a specific embodiment of external system 750. Asillustrated in FIG. 8, external system 850 is a patient managementsystem including an external device 880, a telecommunication network882, and a remote device 884. External device 880 is placed within thevicinity of an implantable medical device and includes externaltelemetry circuit 756 to communicate with the implantable medical devicevia telemetry link 552. Remote device 884 is in one or more remotelocations and communicates with external device 880 through network 882,thus allowing the physician or other caregiver to monitor and treat thepatient from a distant location and/or allowing access to varioustreatment resources from the one or more remote locations. In oneembodiment, as illustrated in FIG. 8, remote device 884 includes userinterface 772. This allows the physician or other caregiver to initiateand/or adjust the cardioprotective stimulation in response to the alarmsignal and/or warning message associated with the ischemia alert signal.

FIG. 9 is a block diagram illustrating an embodiment of stimulationelectrodes for cardioprotective stimulation. An electrode system fordelivering cardioprotective electrical stimulation pulses includes twoor more stimulation electrodes. FIG. 9 illustrates examples ofstimulation electrodes that allow delivery of cardioprotectiveelectrical stimulation pulses to non-ischemic regions of heart 101 andtissue surrounding implantable medical device 910, which represents aspecific embodiment of implantable medical device 110 or 510. In variousembodiments, two or more stimulation electrodes are selected fromelectrodes including, but not limited to, those illustrated in FIG. 9.The selection of the stimulation electrodes is determined by theintended one or more stimulation sites and/or the need to limit thetissue response to a region in close proximity to the one or morestimulation sites.

In one embodiment, one or more pacing electrodes of a lead system 908are used as one or more stimulation electrodes for the delivery ofcardioprotective electrical stimulation pulses. Lead system 908 is aspecific embodiment of lead system 508 and, as shown in FIG. 9 forillustrative purposes, includes an atrial lead 908A and a ventricularlead 908B. The one or more stimulation electrodes are selected from, forexample, a tip electrode 907A of atrial lead 908A, a ring electrode 909Aof atrial lead 908A, a tip electrode 907B of ventricular lead 908B, anda ring electrode 909B of ventricular lead 908B. In one embodiment, theelectrode(s) selected for delivering the cardioprotective electricalstimulation pulses are remote from ischemic region 103. Leads 908A-Beach have a proximal end connected to implantable medical device 910 anda distal end for intracardiac or epicardial placement. Each tipelectrode is located in the distal end of a lead. Each ring electrode islocated near the distal end, at a predetermined distance from the tipelectrode. In one specific embodiment, atrial lead 908A is an RA lead,and ventricular lead 908B is an RV lead. In another specific embodiment,atrial lead 908A is an RA lead, and ventricular lead 908B is an LV lead.In another specific embodiment, lead system 908 includes only one ormore atrial leads. In another specific embodiment, lead system 908includes only one or more ventricular leads. In other specificembodiments, lead system 908 includes more than one atrial lead and/ormore than one ventricular lead.

Implantable medical device 910 includes a hermetically sealed can 991 tohouse its circuit. Can 991 has an outer surface that is contact withbody tissue when implantable medical device 910 is implanted. Can 991includes or provides for a base of a can electrode 994 that isselectable as one of the stimulation electrodes for the delivery ofcardioprotective electrical stimulation pulses. At least a portion ofthe outer surface of can 991 is made of electrically conductivematerial. In one embodiment, can 991 is used as can electrode 994. Inone specific embodiment, can electrode 994 includes at least oneconductive portion of can 991. In another embodiment, can electrode 994is incorporated onto the outer surface of can 991 and is electricallyinsulated from any conductive portion of can 991 using a non-conductivelayer. In one specific embodiment, a hermetically sealed feedthroughincluding a conductor provides for an electrical connection between canelectrode 994 and the circuit housed in can 991.

A header 992 is attached to can 991 and includes connectors providingfor electrical access to the circuit housed in can 991. In oneembodiment, one or more header electrodes 996A-B are incorporated intothe header. Header electrodes 996A-B are each selectable as one of theelectrodes for the delivery of cardioprotective electrical stimulationpulses.

In one embodiment, two or more concentric electrodes 997A-C areincorporated onto the outer surface of can 991. Each of concentricelectrodes 997A-C is selectable as one of the stimulation electrodes forthe delivery of cardioprotective electrical stimulation pulses.Concentric electrodes 997A-C are insulated from the conductive portionof can 991 with a non-conductive layer and connected to the circuithoused in can 991 via hermetically sealed feedthroughs. In oneembodiment, two stimulation electrodes, including an inner electrode andan outer electrode, are selected from concentric electrodes 997A-C forthe delivery of cardioprotective electrical stimulation pulses. Thislimits the tissue response to the stimulation to a region in closeproximity to the selected stimulation electrodes. In one embodiment, theouter electrode has a ring shape. In another embodiment, the outerelectrode has a shape approaching the contour of can 991. In oneembodiment, concentric electrodes 997A-C are incorporated onto the sideof can 991 that is in contact with the epimysium of pectoral muscle whenimplantable medical device 910 is implanted.

In one embodiment, implantable medical device 910 includes an antenna993 for the far-field RF telemetry. Antenna 993 is electricallyconnected to the circuit housed in can 991. In one embodiment, antenna993 projects from header 992 and extends along one side of can 991. Inone embodiment, antenna 993 includes a metal conductor with a distalportion exposed for functioning as an antenna electrode 998, which isselectable as one of the stimulation electrodes for the delivery ofcardioprotective electrical stimulation pulses.

It is to be understood that the electrodes illustrated in FIG. 9 areintended to be examples but not limitations. Other electrodeconfigurations are usable as long as they allow delivery of thecardioprotective electrical stimulation pulses to the one or morestimulation sites. In one embodiment, the stimulation electrodes for thedelivery of cardioprotective electrical stimulation pulses are selectedfrom the electrodes in one or more leads of lead system 908 (e.g.,electrodes 907A, 909A, 907B, and 909B). According to the present subjectmatter, for the purpose of delivering the cardioprotective electricalstimulation pulses, the stimulation electrodes may be remote fromischemic region 103. In another embodiment, the stimulation electrodesfor the delivery of cardioprotective electrical stimulation pulses areimplantable subcutaneous electrodes. Examples of such implantablesubcutaneous electrodes include, but are not limited to electrodesincorporated onto implantable medical device 910, such as can electrode994, header electrodes 996A-B, concentric electrodes 997A-C, and antennaelectrode 998. In a specific embodiment, implantable medical device 910is for implantation in the pectoral area. Stimulation electrodes areselected for delivering cardioprotective electrical stimulation pulsesto cause contraction of the pectoral muscle.

FIG. 10 is a flow chart illustrating an embodiment of a method forcardioprotective stimulation. In one embodiment, the method is performedby system 100, including its various embodiments discussed withreference to FIGS. 1-9.

A cardioprotective stimulation signal is received at 1000. Thecardioprotective stimulation signal is a triggering signal forinitiating a cardioprotective stimulation sequence during which acardioprotective stimulation therapy is delivered to protect a heartfrom ischemic damage. In one embodiment, the cardioprotectivestimulation signal is issued in response to a detection of a cardiacischemic event. In another embodiment, the cardioprotective stimulationsignal is produced in response to a command issued by a physician orother caregiver or a patient. The command is issued in response to anischemic event that has occurred, is occurring, or is anticipated tooccur.

In response to the received cardioprotective stimulation signal, thecardioprotective stimulation sequence is timed at 1010. Thecardioprotective stimulation sequence includes alternating stimulationand non-stimulation periods. Each stimulation period has a stimulationduration during which one or more stimuli are delivered. Eachnon-stimulation period has a non-stimulation duration during which nostimulus is delivered. The one or more stimuli elicit a cardioprotectiveeffect to protect the heart from tissue damage associated with cardiacischemic events.

The one or more stimuli are delivered to one or more stimulation sitesto elicit the cardioprotective effect at 1020. The one or morestimulation sites include at least one site that is remote from theischemic region(s) in the heart. In one embodiment, the one or morestimulation sites include at least one site that is remote from theheart.

FIG. 11 is a flow chart illustrating a specific embodiment of the methodfor cardioprotective stimulation. In one embodiment, the method isperformed by system 100, including its various embodiments discussedwith reference to FIGS. 1-9.

A cardiac ischemic event is detected at 1100. In one embodiment, one ormore physiological signals are sensed, and the cardiac ischemic event isdetected from the one or more physiological signals by running anautomatic ischemia detection algorithm. In one embodiment, an ischemiaalert signal is produced to indicate the detection of the ischemic eventto the physician or other caregiver and/or the patient.

A cardioprotective stimulation command is received at 1110. Thecardioprotective stimulation command is issued by the physician or othercaregiver or the patient. For example, the physician or other caregivermay issue the cardioprotective stimulation command after determiningthat the patient is at risk of cardiac ischemia, including MI. Thepatient having a cardiovascular disorder may issue the cardioprotectivestimulation command when chest pain is felt. The physician or othercaregiver or the patient may also issue the cardioprotective stimulationcommand upon receiving the ischemia alert signal.

In response to either one or both of the detection of the cardiacischemic event or the reception of the cardioprotective stimulationcommand, one or more cardioprotective stimulation signals are producedat 1120. In one embodiment, a postconditioning signal is produced inresponse to the detection of the cardiac ischemic event. In a specificembodiment, the postconditioning signal is produced when a post-ischemiatime interval expires. The post-ischemia time interval starts when theend of the cardiac ischemic event is detected and is up to approximately10 minutes, with approximately 30 seconds being a specific example. In aspecific embodiment, the post-ischemia time interval is chosen such thatthe postconditioning stimulation sequence is initiated during thereperfusion phase following the cardiac ischemic event. In a furtherembodiment, a plurality of preconditioning signals is also produced inresponse to the detection of the cardiac ischemic event. Thepreconditioning signals are produced after the end of the cardiacischemic event is detected and the postconditioning stimulation sequenceis completed. In a specific embodiment, the preconditioning signals areproduced according to a programmed preconditioning schedule, such as ona periodic basis using a predetermined period. The predetermined periodis in a range of approximately 24 hours to 72 hours, with approximately48 hours being a specific example. In another embodiment, the one ormore cardioprotective stimulation signals are produced in response tothe detection of the cardioprotective stimulation command. In a specificembodiment, a postconditioning signal and a plurality of preconditioningsignals are produced in response to the detection of thecardioprotective stimulation command. In another specific embodiment, apostconditioning signal is produced when the detected cardioprotectivestimulation command is a postconditioning command, and one or morepreconditioning signals are produced when the detected cardioprotectivestimulation command is a preconditioning command.

In response to the one or more cardioprotective stimulation signals, oneor more cardioprotective stimulation sequences are timed at 1130. In oneembodiment, in response to a received postconditioning signal, apostconditioning stimulation sequence is timed. The postconditioningstimulation sequence includes alternating postconditioning stimulationand non-stimulation periods. Each postconditioning stimulation periodhas a postconditioning stimulation duration during which one or morestimuli are delivered. Each postconditioning non-stimulation periods hasa postconditioning non-stimulation duration during which no stimulus isdelivered. In one embodiment, in response to each receivedpreconditioning signal, a preconditioning stimulation sequence is timed.Each preconditioning stimulation sequence includes alternatingpreconditioning stimulation and non-stimulation periods. Eachpreconditioning stimulation period has a preconditioning stimulationduration during which the one or more stimuli are delivered. Eachpreconditioning non-stimulation period has a preconditioningnon-stimulation duration during which no stimulus is delivered.

The one or more stimuli are delivered during each postconditioning orpreconditioning stimulation period to elicit a cardioprotective effectagainst cardiac ischemia at 1140. The one or more stimuli are deliveredto one or more stimulation sites in or on the patient's body. In oneembodiment, the one or more stimulation sites are remote from anycardiac ischemic region. In a specific embodiment, the one or morestimulation sites are remote from the patient's heart. In variousembodiments, the one or more stimuli create a physiologic stress in theone or more stimulation sites, create a local ischemic condition in theone or more stimulation sites, and/or cause a release of one or morecardioprotective paracrine factors. Examples of the one or more stimuliinclude one or more electrical stimuli, one or more mechanical stimuli,one or more chemical stimuli, one or more biological stimuli, one ormore optical stimuli, one or more thermal stimuli, and one or moreacoustic stimuli.

One or more stress-indicating signals are sensed at 1150. Eachstress-indicating signal indicates a level of physiologic stress createdby the one or more stimuli. Examples of such stress-indicating signalsinclude electrograms indicative of change in cardiac ischemia statecaused by the one or more stimuli, a strain gauge signal indicative ofmuscular response to the one or more stimuli, a chemical sensor signalindicative of a chemical response to the one or more stimuli, and asignal indicative of exertion level. Examples of the signal indicativeof exertion level include a signal indicative of blood pH value, asignal indicative of oxygen saturation, a respiratory signal indicativeof minute ventilation, a respiratory signal indicative of respiratoryrate, a signal indicative time intervals between selected cardiacevents, a signal indicative of body temperature, a signal indicative ofblood temperature, and a signal indicative of myocardial temperature.

The delivery of the one or more stimuli is adjusted using the sensed oneor more stress-indicating signals at 1160. The adjustment ensures thatthe intended cardioprotective effect is elicited by the one or morestimuli.

The method of cardioprotective stimulation is illustrated in FIGS. 10and 11 as an example but not a restriction. The present subject matterprovides a method for protecting a cardiac or non-cardiac region in abody from ischemic damage by delivering stimulation to one or morestimulation sites remote from the injured region. The injured region isa result from cardiac ischemia or non-cardiac ischemia such as ischemicstroke, ischemic renal failure, ischemia in the central nervous system,and ischemia in the skeletal muscle. The one or mote stimulation sitesincludes cardiac and non-cardiac sites. That is, the present subjectmatter provides for a method for protecting a cardiac region fromischemic damage by delivering stimulation to one or more stimulationsites remote from the heart, as well as a method for protecting anon-cardiac region from ischemic damage by delivering stimulation to oneor more stimulation sites in or on the heart.

FIGS. 12 and 13 illustrate various timing intervals discussed above. Thetiming of the cardioprotective stimulation sequences is illustrated inFIGS. 12 and 13 as an example, but not as a restriction.

FIG. 12 is an illustration of an embodiment of timing ofcardioprotective stimulation sequences including a postconditioningstimulation sequence following by preconditioning stimulation sequences.A postconditioning stimulation sequence is initiated in response to atherapy initiation event, such as a detection of a cardiac ischemicevent or a reception of a cardioprotective stimulation command. A timeinterval 1200 starts with the therapy initiation event. When timeinterval 1200 expires, the postconditioning stimulation sequence isinitiated. In one embodiment, the therapy initiation event is thedetection of the cardiac ischemic event, and time interval 1200 is apost-ischemia time interval that starts at the end of the ischemicevent. The postconditioning stimulation sequence has a postconditioningsequence duration 1220. Then, preconditioning stimulation sequences areinitiated on a periodic basis each with a predetermined period 1210. Thepreconditioning stimulation sequences each have a preconditioningsequence duration 1230.

FIG. 13 is an illustration of an embodiment of timing of stimulation andnon-stimulation periods during a cardioprotective stimulation sequence.The cardioprotective stimulation sequence has a sequence duration 1360and includes alternating stimulation periods 1340 and non-stimulationperiods 1350. One or more stimuli are delivered during each ofstimulation periods 1340. No stimulus is delivered during each ofnon-stimulation periods 1350.

Two pairs of alternating stimulation period 1340 and non-stimulationperiod 1350 are illustrated in FIG. 13 for illustrative but notrestrictive purposes. In various embodiments, a cardioprotectivestimulation sequence may include one pair of stimulation period 1340 andnon-stimulation period 1350, two pairs of stimulation period 1340 andnon-stimulation period 1350, or more than two pairs of stimulationperiod 1340 and non-stimulation period 1350.

In one embodiment, the cardioprotective stimulation sequence is apostconditioning stimulation sequence including alternatingpostconditioning stimulation and non-stimulation periods. Sequenceduration 1360 represents postconditioning sequence duration 1220.Stimulation periods 1340 each represent a postconditioning stimulationperiod having a postconditioning stimulation duration. Non-stimulationperiods 1350 each represent a postconditioning non-stimulation periodhaving a postconditioning non-stimulation duration. In anotherembodiment, the cardioprotective stimulation sequence is apreconditioning stimulation sequence including alternatingpreconditioning stimulation and non-stimulation periods. Sequenceduration 1360 represents preconditioning sequence duration 1230.Stimulation periods 1340 each represent a preconditioning stimulationperiod having a preconditioning stimulation duration. Non-stimulationperiods 1350 each represent a preconditioning non-stimulation periodhaving a preconditioning non-stimulation duration.

The timing of the cardioprotective stimulation sequences as illustratedin FIGS. 12 and 13 may also be applied as a remote conditioningstimulation sequence for protecting a non-cardiac region by pacing theheart. In one embodiment, a postconditioning pacing sequence isinitiated in response to a therapy initiation event, such as a detectionof a non-cardiac ischemic event or a reception of a remote conditioningpacing command. A time interval starts with the therapy initiationevent. When the time interval expires, a postconditioning pacingsequence is initiated. In one embodiment, the therapy initiation eventis the detection of the non-cardiac ischemic event, the time interval isa post-ischemia time interval that starts at the end of the ischemicevent. The postconditioning pacing sequence has a postconditioningpacing duration. Then, preconditioning pacing sequences are initiated ona periodic basis each with a predetermined period. The preconditioningpacing sequences each have a preconditioning sequence duration. Thepostconditioning and preconditioning sequences each have a sequenceduration and include alternating pacing and non-pacing periods. Pacingpulses are delivered during each of the pacing periods at a rate that issufficiently high to induce cardiac ischemia. No pacing pulse isdelivered during each of non-pacing periods.

It is to be understood that the above detailed description is intendedto be illustrative, and not restrictive. Other embodiments will beapparent to those of skill in the art upon reading and understanding theabove description. The scope of the invention should, therefore, bedetermined with reference to the appended claims, along with the fullscope of equivalents to which such claims are entitled.

1. A system for stimulating at least one stimulation site in a bodyhaving a heart, the at least one stimulation site remote from the heart,the system comprising: an implantable stimulation output deviceconfigured for delivering non-cardiac stimulation to the at least onestimulation site; and an implantable medical device including: acardioprotective stimulation module coupled to the implantablestimulation output device, the cardioprotective stimulation moduleadapted to deliver one or more non-cardiac stimuli to the at least onestimulation site through the implantable output device, the one or morenon-cardiac stimuli creating a physiologic stress at the at least onestimulation site without causing myocardial contraction in the heart,the physiologic stress capable of eliciting a cardioprotective effectthat protects the heart from tissue damage caused by cardiac ischemia;and a cardioprotective stimulation controller coupled to thecardioprotective stimulation module, the cardioprotective stimulationcontroller including: a stimulation initiator including an ischemiadetector adapted to detect an end of a cardiac ischemic event, thestimulation initiator adapted to produce cardioprotective stimulationsignals in response to a detection of the end of the cardiac ischemicevent, the cardioprotective stimulation signals each initiating acardioprotective stimulation sequence; and a stimulation timer adaptedto time the cardioprotective stimulation sequence in response to each ofthe cardioprotective stimulation signals, the cardioprotectivestimulation sequence including alternating stimulation andnon-stimulation periods, the stimulation periods each having astimulation duration during which the one or more non-cardiac stimuliare delivered, the non-stimulation periods each having a non-stimulationduration during which none of the one or more non-cardiac stimuli isdelivered.
 2. The system of claim 1, wherein the implantable stimulationoutput device comprises at least one stimulation electrode, and thecardioprotective stimulation module comprises an electrical stimulationcircuit adapted to deliver one or more non-cardiac electrical stimulithrough the at least one stimulation electrode.
 3. The system of claim2, wherein the implantable medical device further comprises a cardiacstimulation circuit to deliver cardiac stimulation pulses to the heart.4. The system of claim 3, wherein the implantable medical devicecomprises an implantable housing configured to house thecardioprotective stimulation module, the cardioprotective stimulationcontroller, and the cardiac stimulation circuit, and wherein the atleast one electrode is incorporated onto the implantable housing.
 5. Thesystem of claim 1, wherein the cardioprotective stimulation modulecomprises a mechanical stimulation device adapted to deliver one or moremechanical stimuli of the one or more non-cardiac stimuli, the one ormore mechanical stimuli creating physical deformation of tissue at theat least one stimulation site.
 6. The system of claim 1, furthercomprising at least one physiological stress sensor adapted to sense astress-indicating signal indicative of a level of the physiologicstress, and wherein the cardioprotective stimulation controller isadapted to control the delivery of the one or more stimuli creating thephysiologic stress using the stress-indicating signal.
 7. The system ofclaim 6, wherein the at least one physiological stress sensor comprisesa cardiac sensing circuit adapted to sense an electrogram.
 8. The systemof claim 6, wherein the at least one physiological stress sensorcomprises a chemical sensor adapted to sense a degree of chemicalreaction to the non-cardiac stimulation.
 9. The system of claim 6,wherein the at least one physiological stress sensor comprises anexertion level sensor to sense an exertion level.
 10. The system ofclaim 9, wherein the exertion level sensor is adapted to sense a pHvalue.
 11. The system of claim 9, wherein the exertion level sensor isadapted to sense an oximetry or plethysmography signal.
 12. The systemof claim 9, wherein the exertion level sensor is adapted to sense arespiratory signal.
 13. The system of claim 9, wherein the exertionlevel sensor is adapted to sense one or more cardiac time intervals. 14.The system of claim 9, wherein the exertion level sensor is adapted tosense one or more of body temperature, blood temperature, and myocardialtemperature.
 15. The system of claim 6, wherein the at least onephysiological stress sensor comprises a strain gauge adapted to measurea degree of muscular contraction.
 16. The system of claim 1, wherein thecardioprotective stimulation module comprises a gene regulatory deviceto deliver a gene regulatory signal controlling a gene expression. 17.The system of claim 1, wherein the cardioprotective stimulation modulecomprises one or more of a mechanical stimulation device to deliver oneor more mechanical stimuli, a chemical stimulation device to deliver oneor more chemical stimuli, a biological stimulation device to deliver oneor more biological stimuli, an optical stimulation device to deliver oneor more optical stimuli, a thermal stimulation device to deliver one ormore thermal stimuli, and an acoustic stimulation device to deliver oneor more acoustic stimuli.
 18. The system of claim 1, wherein thestimulation initiator is adapted to produce a postconditioning signal inresponse to a detection of the end of the cardiac ischemic event, thepostconditioning signal being one of the cardioprotective stimulationsignals.
 19. The system of claim 18, wherein the stimulation initiatoris further adapted to produce a plurality of preconditioning signals inresponse to the detection of the end of the cardiac ischemic event, thepreconditioning signals each being one of the cardioprotectivestimulation signals.
 20. The system of claim 19, wherein the stimulationinitiator is adapted to produce the plurality of preconditioning signalson a periodic basis using a predetermined period in a range ofapproximately 24 hours to 72 hours.
 21. The system of claim 1, whereinthe stimulation initiator comprises a stimulation command detector todetect a cardioprotective stimulation command and is adapted to produceone or more of the cardioprotective stimulation signals in response tothe detection of the cardioprotective stimulation command.
 22. Thesystem of claim 21, further comprising an external systemcommunicatively coupled to the implantable medical device, the externalsystem adapted to transmit the cardioprotective stimulation command. 23.The system of claim 22, wherein the external system comprises: a userinterface device to receive a user command; and an external controllerto produce the cardioprotective stimulation command in response to theuser command.
 24. The system of claim 23, wherein the external systemcomprises a handheld device.
 25. The system of claim 1, wherein thecardioprotective stimulation module comprises an electrical stimulationdevice adapted to deliver one or more electrical stimuli.
 26. The systemof claim 1, wherein the cardioprotective stimulation module comprises achemical stimulation device adapted to deliver one or more chemicalstimuli.
 27. The system of claim 1, wherein the cardioprotectivestimulation module comprises a biological stimulation device adapted todeliver one or more biological stimuli.
 28. The system of claim 1,wherein the cardioprotective stimulation module comprises an opticalstimulation device adapted to deliver one or more optical stimuli. 29.The system of claim 1, wherein the cardioprotective stimulation modulecomprises a thermal stimulation device adapted to deliver one or morethermal stimuli.
 30. The system of claim 1, wherein the cardioprotectivestimulation module comprises and an acoustic stimulation device adaptedto deliver one or more acoustic stimuli.
 31. A system for stimulating atleast one stimulation site in a body having a heart, the at least onestimulation site remote from the heart, the system comprising: animplantable stimulation output device configured for deliveringnon-cardiac stimulation to the at least one stimulation site; and animplantable medical device including: a cardioprotective stimulationmodule coupled to the implantable stimulation output device, thecardioprotective stimulation module adapted to deliver one or morenon-cardiac stimuli to the at least one stimulation site through theimplantable output device, the one or more non-cardiac stimuli creatinga physiologic stress at the at least one stimulation site withoutcausing myocardial contraction in the heart, the physiologic stresscapable of eliciting a cardioprotective effect against cardiac ischemia;and a cardioprotective stimulation controller coupled to thecardioprotective stimulation module, the cardioprotective stimulationcontroller including: a stimulation initiator including an ischemiadetector adapted to detect an end of a cardiac ischemic event, thestimulation initiator adapted to produce cardioprotective stimulationsignals after the end of the cardiac ischemic event is detected, thecardioprotective stimulation signals each initiating a cardioprotectivestimulation sequence; and a stimulation timer adapted to time thecardioprotective stimulation sequence in response to each of thecardioprotective stimulation signals, the cardioprotective stimulationsequence including alternating stimulation and non-stimulation periods,the stimulation periods each having a stimulation duration during whichthe one or more non-cardiac stimuli are delivered, the non-stimulationperiods each having a non-stimulation duration during which none of theone or more non-cardiac stimuli is delivered, wherein the stimulationinitiator is adapted to produce a postconditioning signal when apost-ischemia time interval expires, the post-ischemia time intervalstarting when the end of the cardiac ischemic event is detected, thepostconditioning signal being one of the cardioprotective stimulationsignals.
 32. A system for stimulating at least one stimulation site in abody having a heart, the at least one stimulation site remote from theheart, the system comprising: an implantable stimulation output deviceconfigured for delivering non-cardiac stimulation to the at least onestimulation site; and an implantable medical device including: acardioprotective stimulation module coupled to the implantablestimulation output device, the cardioprotective stimulation moduleadapted to deliver one or more non-cardiac stimuli to the at least onestimulation site through the implantable output device, the one or morenon-cardiac stimuli creating a physiologic stress at the at least onestimulation site without causing myocardial contraction in the heart,the physiologic stress capable of eliciting a cardioprotective effectagainst cardiac ischemia; and a cardioprotective stimulation controllercoupled to the cardioprotective stimulation module, the cardioprotectivestimulation controller including: a stimulation initiator including anischemia detector adapted to detect an end of a cardiac ischemic event,the stimulation initiator adapted to produce cardioprotectivestimulation signals after the end of the cardiac ischemic event isdetected, the cardioprotective stimulation signals each initiating acardioprotective stimulation sequence; and a stimulation timer adaptedto time the cardioprotective stimulation sequence in response to each ofthe cardioprotective stimulation signals, the cardioprotectivestimulation sequence including alternating stimulation andnon-stimulation periods, the stimulation periods each having astimulation duration during which the one or more non-cardiac stimuliare delivered, the non-stimulation periods each having a non-stimulationduration during which none of the one or more non-cardiac stimuli isdelivered, wherein the stimulation initiator is adapted to produce apostconditioning signal within approximately 10 minutes after the end ofthe cardiac ischemic event is detected, the postconditioning signalbeing one of the cardioprotective stimulation signals.